This invention relates to a method of inhibiting the production of cytokines, particularly inhibiting the production of tumor necrosis factor.alpha., interleukin-10, and macrophage inflammatory protein-1.alpha., in a mammal, including a human, in need thereof which involves administering to such mammal an effective, cytokine production inhibiting amount of a polymethoxylated flavone.
Flavonoids are widely distributed in the plant kingdom and as many as 4000 flavonoid-related compounds have been described (Brandi, M. L., Bone Miner., 1992, (Suppl. 1), S3-14). Ingested at hundreds of mg per day in the Western diet, flavonoids appear to have several beneficial effects on human health. Of particular interest are the flavonoids derived from citrus, many of which exhibit anticancer, anticarcinogenic, antiviral, antioxidant, antithrombogenic, and antiatherogenic properties (Benavente-Garcia, O., et al., J. Agr. Food Chem., 45: 4505-4515 (1997)). Polymethoxylated flavones from citrus have been shown to reduce the invasiveness of tumors in animal models (Vermeulen, S., et al., Pathology Res. Practice, 192: 694-707 (1996)) and to induce the differentiation of myeloid leukemic cells and suppress proliferation while promoting apoptosis (Sugiyama, S., et al., Chem. Pharm. Bull., 41: 714-719 (1993); Hirano, T., et al., Brit. J. Cancer, 72: 11380-1388 (1995)). These polymethoxylated flavones have further been shown to reduce lymphocyte proliferation (Mookerjee, B. K., et al., J. Immunopharmacol., 8:371-392 (1986)), platelet aggregation (Beret, A., et al., in Plant Flavonoids in Biology and Medicine II: Biochemical, Cellular, and Medicinal Properties; Cody, V., Middleton, E. Jr., Harborne, J. B., Beretz, A., Eds.; Progress in Clinical and Biological Research 280; Alan R. Liss Inc.: New York, 1988; p 187-200), and to suppress ethanol-induced gastric hemorrhagic lesions (Takase, H., et al.,. Japan. J. Pharmacol., 66: 139-147 (1994)), while promoting chloride secretion by human colonic epithelial cells (Nguyen, T. D., et al., J. Nutrition, 123: 259-268 (1993)). The antiinflammatory properties of dietary flavonoids have also received considerable attention. Select hydroxylated flavones block adhesion molecule biosynthesis by cytokine-induced endothelial cells (Baloch, Z., et al., Cell Immunol., 160: 98-103 (1995); Gerritsen, M. E., et al., Am. J. Pathol., 147: 278-292 (1995)). In other studies, flavonoids have been shown to block activation-induced degranulation of neutrophils and mast cells (Middleton, E., Jr., et al., Biochem. Pharmacol., 43: 1167-1179 (1992)). A formulation of citrus flavonoids has been shown to block capillary leakage and leukocyte infiltration in animal models (Bouskela, E., et al., Angiology, 48: 391-399 (1997); Friesenecker, B., et al.,. Int. J. Microcirc., (suppl. 1), 17-21 (1995).
Central to many aspects of inflammation are the cytokines which behave as autocrine or paracrine protein factors. In particular, the cytokine, tumor necrosis factor-.alpha. (TNF.alpha.), drives many critical components of inflammatory processes (Feldmann, M., et al., Annu. Rev. Immunol., 14: 397-440 (1996); Moreland, L. W., N. Engl. J. Med., 337:141-147 (1997)). Monocytes are a major cellular source of TNF.alpha. and other cytokines. Recently the main flavanone glycoside in grapefruit, naringin, has been reported to suppress lipopolysaccharide-induced TNF.alpha. release and liver injury in mice (Kawaguchi, K., et al., Eur. J. Pharmacol., 368: 245-250 (1999)). However, apparently there have been no reports of polymethoxylated flavonoids inhibiting the production of cytokines (e.g., tumor necrosis factor.alpha., interleukin-10, macrophage inflammatory protein-1.alpha.).